Intermediates for the synthesis of polypropionate antibiotics

ABSTRACT

The invention relates to intermediate compounds of the formula 
                         
wherein R 1  is H or a protecting group, R 2  and R 3  each independently represent H, methyl, or a leaving group, provided that at least one, but not both, of R 2  and R 3  is a leaving group. The intermediate compounds are useful for the synthesis of discodermolide, its derivatives, and related compounds.

The present invention was made in part with government support underGrant No. 5R01CA87503 awarded by the National Institutes of Health. TheUnited States government has certain rights in this invention.

BACKGROUND OF THE INVENTION

Discodermolide, more specifically referred to as (+)-discodermolide, isa microtubule-stabilizing drug which is found naturally in the Caribbeansponge Discodermia dissolute. Discodermolide has attracted widespreadattention because of its known potent inhibition of tumor cell growth.The structure of discodermolide is shown below:

As evidenced by the structure above, discodermolide is a structurallycomplex molecule. Contributing to its complexity are thirteen chiralcenters, grouped as a stereotetrad (four contiguous chiral centers, C-2to C-5)), an isolated chiral center (C-7), a stereotriad (threecontiguous chiral centers (C-10 to C-12), and a stereopentad (fivecontiguous chiral centers, C-16 to C-20), and four olefinic bonds, threeof which have specific geometry. The C-10 to C-12 stereotriad has syn,anti relative stereochemistry. This stereotriad (syn, anti) is alsofound within the stereotetrad and within the stereopentad.

The isolation of discodermolide from natural sources has not resulted incommercially meaningful quantities of the drug. Accordingly, thereremains a continuing effort to find an efficient synthesis ofdiscodermolide.

Because of the structural complexity of discodermolide, its synthesishas proven to be a formidable task. The synthesis of multigramquantities of discodermolide reported by Novartis in March 2004 requiredmore than 20 steps in the longest linear sequence (more than 30 steps intotal) and twenty months of work. See M. Freemantle, “Scaled-UpSynthesis of Discodermolide,” Chemical & Engineering News, Mar. 1, 2004,pp. 33-35.

The Novartis synthesis as reported, like other published totalsyntheses, was based on the elaboration of the well-known chiral fungalproduct, methyl (R)-2-methyl-3-hydroxypropionate (the “Roche ester”), asthe source of chirality for all three key intermediates.

Recently, syntheses of key intermediates in which the source ofchirality was a chiral auxiliary were reported. See Dias, Luiz C.; Bau,Rosana Z.; de Sousa, Marcio A.; Zukerman-Schpector, J. “High 1,5-AntiStereoinduction in Boron-Mediated Aldol Reactions of Methyl Ketones”Organic Letters (2002), 4(24), 4325-4327 and Day, Billy W.; Kangani,Cyrous O.; Avor, Kwasi S. “Convenient syntheses of(2R,3S,4R)-3-(tert-butyldimethylsilanyloxy)-2,4-dimethyl-5-oxopentanoicacid methoxymethylamide from methacrolein. Preparation of C1-C7 andC17-C24 fragments of (+)-discodermolide.” Tetrahedron: Asymmetry (2002),13(11), 1161-1165. This approach was incorporated in the Novartisscale-up studies; see Loiseleur, Olivier; Koch, Guido; Wagner, Trixie.“A Practical Building Block for the Synthesis of Discodermolide.”Organic Process Research & Development (2004), 8(4), 597-602 Also,recently, Myles and coworkers at Kosan prepared Smith's keyintermediate, the common precursor “CP” by chemical modification of afermentation product from a genetically engineered Streptomyces, seeBurlingame, Mark A.; Mendoza, Esteban; Ashley, Gary W.; Myles, David C.“Synthesis of discodermolide intermediates from engineered polyketides”Tetrahedron Letters (2006), 47(7), 1209-1211.

There are other biologically active compounds which share some of thestructural features of discodermolide. For example, the calyculins,natural products isolated from the marine sponge Discodermia calyx areinhibitors of serine-threonine phosphatase. Calyculins A and B are shownbelow. The encircled part of the structure shows a stereotetrad, thatcontains an anti, anti stereotriad at C-10 to C-12.

Likewise, the macrolide antitumor agent dictyostatin contains two syn,anti stereotriads, encircled in the picture, one of which is part of astereotetrad.

Accordingly, there is a clear need for more efficient ways to producepolypropionate antibiotics in which there are stereotriad regions. Suchimproved syntheses can be realized by, for example, providing newchemical intermediates. Particularly beneficial for this purpose are newintermediates which conveniently provide the anti, syn stereotriad thatis contained, for example, in the C8 to C14 portion of discodermolide.Also particularly beneficial are schemes that rely on asymmetriccatalysis, rather than on expensive chiral starting materials such asthe Roche ester or on chiral auxiliaries for the introduction ofchirality.

SUMMARY OF THE INVENTION

These, and other objectives as will be apparent to those of ordinaryskill in the art, have been achieved by providing novel intermediatecompounds of the formula:

In formula (1), R¹ is H or a protecting group, and R² and R³ eachindependently represents H, methyl, or a leaving group, provided that atleast one of R² and R³ is a leaving group.

In another embodiment, the invention relates to a compound having theformula:

wherein:

R¹ represents H or a protecting group;

R¹⁰ represents H or an alkyl group having 1-12 carbon atoms optionallysubstituted with one or more aryl groups, amino groups, halo groups, orOR¹⁴ wherein R¹⁴ represents an alkyl group having 1-12 carbon atoms; and

R¹¹ and R¹² independently represent an alkyl group having 1-12 carbonatoms optionally substituted with one or more aryl groups, amino groups,halo groups, or OR¹⁴ wherein R¹⁴ represents an alkyl group having 1-12carbon atoms; and wherein R¹¹ and R¹² may be connected to form a ring.

The intermediate compounds of formula (1) are useful for the synthesisof discodermolide, its derivatives, and related compounds.

DETAILED DESCRIPTION

The invention relates to compounds represented by the formula

In one embodiment, R¹ in formula (1) represents hydrogen (H).

In another embodiment, R¹ represents a protecting group. The protectinggroup can be essentially any group suitable for the protection of analcohol group as known in the art. In this specification, the phrase“protecting group” indicates any functionality that is used to replace ahydrogen on an alcohol and which can be removed with restoration of thehydrogen without altering the structure of the remainder of themolecule. Some examples are given below, but they are not meant to beinclusive.

An example of a class of suitable protecting groups for R¹ includes theclass of silyl protecting groups. The class of silyl protecting groups,including silyl ether protecting groups, can be represented according tothe formula:—Si(O_(x)R⁴)(O_(y)R⁵)(O_(z)R^(6a))

In the formula above for silyl ether protecting groups, R⁴, R⁵, and R⁶aeach independently represents an alkyl group or an aryl group. The alkylgroups are preferably linear or branched, preferably having one to fourcarbon atoms, typically methyl, ethyl, isopropyl, butyl, and tertiarybutyl. The aryl groups of R⁷ are preferably phenyl, pyridinyl, pyrrolyl,or furanyl.

The subscripts x, y, and z independently represent 0 or 1. When x, y, orz is 0, the oxygen atom to which the subscript is associated is absent.When x, y, or z is 1, the oxygen atom to which the subscript isassociated, is present.

Any two alkyl groups of O_(x)R⁴, O_(y)R⁵, and O_(z)R^(6a), for example,R⁴ and R⁵, are optionally connected to form a silicon-containing ring.The carbon-carbon bond formed accompanies removal of a hydrogen atomfrom each carbon atom joined. The values of x and y are preferably both0.

The size of the silicon-containing ring resulting from interconnectionof two alkyl groups of R⁴, R⁵, and R^(6a) depends on the size of the Rgroups that form the ring, and the value of x, y, and, as the case maybe, z. Preferably, the ring includes two to six ring carbon atoms inaddition to the silicon atom. For example, in one embodiment, R⁴ and R⁵are both methyl groups and x and y are both 0. The methyl groups can beconnected via their carbon atoms to form a silacyclopropane ring. Inanother embodiment, R⁴ and R⁵ are both ethyl groups and x and y are both0. Depending on the connecting carbon atoms chosen, the ethyl groups canbe connected to form a silacyclopentane ring or a2-methylsilacyclobutane ring.

Some examples of silyl protecting groups according to the formula abovefor silyl ether protecting groups wherein x, y, and z are all 0 includetriethylsilyl, tri-(n-propyl)silyl, triisopropylsilyl,tri-(n-butyl)silyl, triisobutylsilyl, t-butyldimethylsilyl (TBS),t-butyldiphenylsilyl, phenyldimethylsilyl, methyldiphenylsilyl,triphenylsilyl.

Some examples of silyl protecting groups according to the formula abovewherein at least one of x, y, and z is 1 include trimethoxysilyl,dimethoxymethylsilyl, methoxydimethylsilyl, ethoxydimethylsilyl,methoxydiethylsilyl, isopropoxydimethylsilyl, phenoxydimethylsilyl,phenoxydiethylsilyl, methyldiphenoxysilyl,[2,4,6-tri-(t-butyl)phenoxy]dimethylsilyl, t-butoxydimethylsilyl,t-butoxydiphenylsilyl, (t-butyl)(methoxy)phenylsilyl, andmethoxydiphenylsilyl.

Another example of a class of useful protecting groups for compounds offormula 1 is the acetal/ketal class. This class of protecting groups canbe represented according to the formula:

R⁶ preferably represents an alkyl group optionally substituted with anaryl group; R⁷ preferably represents hydrogen, an alkyl group, or anaryl group; and R⁸ preferably represents hydrogen or an alkyl group. Thealkyl groups of R⁶, R⁷, and R⁸ are linear or branched, preferably havingone to four carbon atoms, typically methyl or ethyl. The alkyl groups ofR⁶ and R⁷ may be joined to form a five or six member saturated ring. Thearyl substituent of R⁶ and the aryl group of R⁷ are preferably phenyl,pyridinyl, pyrrolyl, or furanyl.

Some preferred acetal/ketal protecting groups include methoxymethyl,ethoxymethyl, tetrahydropyranyl, and benzyloxymethyl. Some additionalprotecting groups in this class include p-methoxybenzyloxymethyl andbeta-trimethylsilyloxyethoxymethyl (SEM) groups.

Another example of a class of suitable protecting groups includesarylmethyl protecting groups, which protect a hydroxyl group byconverting it to an arylmethyl ether. The aryl group may be phenyl,pyridinyl, pyrrolyl, or furanyl, optionally substituted with methoxy,ethoxy, nitro, or halo (F, Cl, Br, or I). Some preferred members of thisclass of protecting groups include benzyl, p-methoxybenzyl, andp-ethoxybenzyl.

Other suitable protecting groups are reviewed in Protecting groups byKocienski, Philip J. Stuttgart; New York: Georg Thieme, c2005 and inProtective groups in organic synthesis by Greene, Theodora W. and Wuts,Peter G. M. New York: Wiley, c1999.

In formula (1), R¹ and R³ each independently represent H, methyl, or aleaving group. At least one of R² and R³ is a leaving group. Preferably,only one of R² and R³ is a leaving group.

For example, R² can be a methyl group or H, and R³ a leaving group; andR³ can be a methyl group or H, and R² a leaving group.

The leaving group is essentially any group capable of being replaced bya carbon substituent under conditions to which the protecting group isstable. For example, the leaving group can be a halogen atom. Somesuitable halogen atoms include chloride, bromide, and iodide.

Alternatively, the leaving group can be organic in nature, such as, forexample, a sulfonate ester group or a phosphorus ester group. Someexamples of sulfonate ester groups include triflate, mesylate, tosylate,and benzenesulfonate. Examples of phosphorus ester groups includephosphates.

In one embodiment, the compounds belong to the class of Z-isomerintermediate compounds. In one example of a Z-intermediate compound, R¹is a protecting group, R³ is a methyl group and R² is a leaving group.These compounds are useful for the synthesis of (+)-discodermolide andits derivatives.

In another embodiment of a Z-intermediate compound, R¹ in formula (1) isa protecting group, while R³ is H and R² is a leaving group. Thesecompounds are intermediates for the synthesis of, inter alia, the14-normethyl analog of discodermolide and its derivatives. Morespecifically, these compounds are intermediates for the synthesis of13,14-cis-14-normethyl discodermolide and its analogs.

The intermediate compounds of formula (1) contain carbons 8 to 14 (i.e.,C8-C14) of discodermolide. The carbon atom that corresponds to C14 ofdiscodermolide is attached to R² and R³ in formula (1). In order toproduce discodermolide, the compounds according to formula (1) must betreated with other compounds which provide the C1-C7 and C15-C24portions of discodermolide. A suitable protocol for doing so is shown inschemes 1-3 below.

The term “discodermolide” as used herein refers to (+)- or(−)-discodermolide as well as any stereoisomeric and structuralderivatives within the scope of the invention. Also included aremixtures of (+)- and (−)-discodermolide in any ratio. For example, themixture can be a racemic mixture of (+)- and (−)-discodermolide.

The E-isomer intermediate compounds are also useful, for example in thesynthesis of the calyculins. Specifically, the E-isomer intermediatescan provide the stereotriad portion of the calyculin compounds. Someexamples of particularly relevant E-isomer intermediate compoundsaccording to formula (1) include those shown below in formulas 1a and 1bbelow.

The compound according to formula (1) contains three adjacentstereocenters, i.e., a stereotriad. For the synthesis of(+)-discodermolide and its derivatives, the compound according toformula (1) is more specifically represented as:

wherein R¹ has the same meaning as above.

An example of a particularly preferred compound according to formula(1c) includes the structures according to formula (1d) and (1e):

wherein MOM represents methoxymethyl.

In addition to the stereoisomeric configuration shown in formula (1c),the invention also includes any of the other possible stereoisomericconfigurations. Other stereoisomeric configurations are useful forproducing the corresponding (−)- or epi-discodermolide derivatives. Forexample, the stereochemically inverted analog of formula (1c), as shownbelow in formula (1f), can be used to make (−)-discodermolide.

The deprotected alcohol compounds, i.e., when R¹ in formula (1) is H,can be used, inter alia, as a storable precursor to the correspondingprotected derivatives. The corresponding alcohols can be represented byformula (1g) below where R² and R³ are as previously defined.

The deprotected alcohol compounds can be synthesized by, for example,deprotection of the corresponding protected compounds by any suitablemeans known in the art. For example, deprotection can be achieved byhydrolysis of an acetal or silyl ether with an acid.

In one embodiment, formula (1) represents any of the stereoisomericcompounds, as described above. In another embodiment, formula (1)represents a mixture, such as a racemic mixture, of two or morecompounds having the structure of formula (1). For example, formula (1)can represent a combination of compounds according to formulas (1c) and(1f).

In addition, when formula (1) represents more than one stereoisomericcompound, the compounds can be in any suitable proportion to each other.For example, a combination of stereoisomeric compounds, such as that offormulas (1c) and (1f) can be in proportions of approximately 50:50,40:60, 30:70, 20:80, 10:90, 5:95, 1:99, and so on.

The synthesis of intermediate compounds according to formula (1) can beaccomplished by any suitable synthetic method known in the art. In apreferred embodiment, the intermediate compounds can be synthesizedaccording to Scheme 1.

The compounds according to formula (1) allow for the convenientsynthesis of discodermolide and its derivatives by methods known in theart. For example, when the building block 1d is used in conjunction withbuilding block 13, available as shown in Scheme 2, discodermolide isconveniently synthesized by the sequence shown in Scheme 3.

As can be seen in scheme 1, compounds having general formula 1 areconveniently prepared from compounds having general formula 8, whereinR¹ has the meaning described above.

For example, compounds having general formula 8 wherein R1 represents H(8g) correspond to formula 1g.

A particular stereochemical isomer of structure 1 can be prepared fromthe corresponding stereochemical isomer of formula 8. For example,compounds having formulas 1d and 1e are conveniently prepared fromcompounds having formulas 8a and 8b, respectively. See scheme 1.

More generally, formula 8c below corresponds to formula 1c above.

Therefore, compounds having formulas 1d and 1e, above, are convenientlysynthesized from compounds having formula 8c when R¹ in 8c representsSi(^(t)Bu)(CH₃)₂ (formula 8d) or MOM (8e), respectively. Theseintermediates are useful in preparing (+)-discodermolide.

Correspondingly, compounds having formula 8f may be used to preparecompounds having formula 1f.

Compounds having formula 1f are useful in preparing (−)-discodermolide.

Preferred methods for fulfilling the reaction steps given above areprovided in the examples below. The examples below are for the purposeof illustration. Accordingly, the scope of the invention is not to be inany way limited by the examples given below.

The Racemic Series (Scheme 1)

EXAMPLE 1 Racemic Cis Allylic Alcohol (3)

A solution of cyclohexanecarboxaldehyde (2) (2.33 g, 20.8 mmol) in 40 mLof THF was cooled to −40° C. 1-Propynylmagnesium bromide (0.5 M in THF,50.0 mL was added dropwise. After adding, the temperature of thereaction mixture was increased to 0° C. and stirred for 2 h. Thereaction was quenched with saturated aqueous ammonium chloride solution.The water phase was extracted with ether (3×20 mL). The combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The crude product was chromatographed (HE: EA=10:1) toprovide 2.78 g (88%) of the propargyl alcohol as an oil. ¹H NMR (300MHz, CDCl₃) 4.10 (m, 1H), 1.85 (d, J=2.1 Hz, 3H), 1.80-1.65 (m, 5H),1.58-1.20 (m, 1H), 1.30-0.98 (m, 6H); ¹³C NMR (300 MHz, CDCl₃) 81.6,79.5, 67.5, 44.4, 28.7, 28.2, 26.5, 26.02, 26.00, 3.7.

A solution of the propargyl alcohol from the above experiment (380 mg,2.5 mmol) in hexane (3 mL) was treated with Pd/CaCO₃ poisoned with Pb,(5% Pd, 30 mg) and quinoline (64 μL). Hydrogen was bubbled through thereaction mixture for 20 min, and the resultant suspension was stirredvigorously for 24 h under 1 atm of H₂. After filtration through Celitewith Et₂O, the solvents were removed in vacuo. Chromatography (HE:EA=10:1) gave racemic alcohol (3) (346 mg, 90%) as a clear liquid. ¹HNMR (300 MHz, CDCl₃) 5.57 (dqd, J=10.2, 6.8, 1.3 Hz, 1H), 5.36 (ddq,J=10.2, 9.4, 1.8 Hz, 1H), 4.14 (dd, J=8.4 Hz, 1.0 Hz, 1H), 1.90 (m, 1H),1.80-1.58 (m, 8H), 1.58-0.80 (m, 6H); ¹³C NMR (300 MHz, CDCl₃) 132.4,126.9, 71.7, 44.3, 29.0, 28.6, 26.8, 26.3, 26.2, 13.7. IR 3365 (broad),2923, 28523, 1449, 1022, 994.

EXAMPLE 2 Racemic Ether (4)

A 100-mL reaction flask was charged with 95% sodium hydride (2.76 g, 109mmol) and 20 mL of dry THF. Racemic alcohol 3 (2.40 g, 15.6 mmol) in 2mL of THF was added dropwise followed by 3-chloro-2-methylpropene (4.24g, 46.8 mmol). The reaction mixture was stirred at reflux overnight andthen cooled to room temperature. Excess sodium hydride was quenched bythe slow addition of 3 mL of water. The resulting mixture was pouredinto water. Ether extracts (30 mL×3) were combined and the resultingorganic solution was dried over MgSO₄, filtered, and concentrated.Chromatography (HE: EA=30:1) produced a colorless oil (2.78 g, 85%). ¹HNMR (300 MHz, CDCl₃) 5.73 (dqd, J=10.2, 6.8, 1.3 Hz, 1H), 5.24 (ddq,10.2, 9.4, 1.8 Hz, 1H), 4.93 (m, 1H), 4.85 (m, 1H), 3.90 (d, J=12.6 Hz,1H), 3.80 (m, 1H), 3.69 (d, J=12.4 Hz, 1H), 1.96 (m, 1H), 1.73 (s, 3H),1.70-1.65 (m, 5H), 1.62 (dd, J=7.1, 2.0 Hz, 3H), 1.58-0.80 (m, 6H); ¹³CNMR (300 MHz, CDCl₃) 143.3, 130.9, 128.1, 112.1, 77.9, 72.0, 43.1, 31.9,29.7, 28.9, 27.0, 26.5, 26.4, 23.0, 20.0, 14.4, 13.9. IR 2971, 2922,2852, 1449, 1085, 896.

EXAMPLE 3 Racemic Dienol (5)

Potassium tert-butoxide (1.0 M in THF, 5.5 mL, 5.5 mmol) was added to aflask under argon and an additional 5.0 mL of THF was added. Thesolution was cooled to −78° C. and ether (4) (5.0 mmol, 1.05 g) wasadded. n-Butyllithium (1.6M in THF, 3.8 mL, 6.1 mmol) was slowly added.The mixture was warmed to −20° C. over 4 h and the stirred 12 h at −20°C. and 2 h at 0° C. The reaction was quenched with water and theresulting mixture was extracted with ether. The organic phase was driedover MgSO₄ and concentrated. Chromatography (HE: EA=10:1) gave acolorless oil (819 mg, 78%). ¹H NMR (300 MHz, CDCl₃) 5.40 (dd, J=16.2,6.6 Hz, 1H), 5.31 (dd, J=16.2, 6.6 Hz, 1H), 4.92 (m, 1H), 4.86 (m, 1H),3.87 (d, J=20.0 Hz, 1H), 2.33 (m, 1H), 1.90 (m, 1H), 1.69 (s, 3H),1.68-1.65 (m, 5H), 1.32-1.05 (m, 6H), 0.97 (d, J=6.9 Hz, 3H); ¹³C NMR(300 MHz, CDCl₃) 146.2, 137.4, 129.9, 112.1, 79.3, 41.0, 40.1, 33.5,33.4, 26.5, 26.4, 18.9, 14.8. IR 3403 (broad), 2965, 2924, 2851, 1448,979, 968, 896.

EXAMPLE 4 Racemic Silyl Ether (6)

A mixture of racemic alcohol 5 (550 mg, 2.62 mmol), imidazole (446 mg,6.55 mmol), t-BuMe₂SiCl (592 mg, 3.93 mmol) and DMAP (80.5 mg, 0.66mmol) in 3 mL of DMF was stirred overnight. The mixture was partitionedbetween ether (50 mL) and water (3×15 mL). The combined water solutionwas extracted with ether (2×25 mL) and then the combined organicsolution was dried over MgSO₄, filtered, and concentrated.Chromatography (HE: EA=30:1) gave a colorless oil (704 mg, 83%). ¹H NMR(300 MHz, CDCl₃) 5.30 (dd, J=16.1, 6.6 Hz, 1H), 5.19 (dd, J=16.1, 6.6Hz, 1H), 4.78 (m, 1H), 4.75 (m, 1H), 3.71 (d, J=7.0 Hz, 1H), 2.17 (m,1H), 1.88 (m, 1H), 1.75-1.64 (m, 4H), 1.63 (s, 3H), 1.32-0.96 (m, 6H),0.94 (d, J=7.0 Hz, 3H), 0.89 (s, 9H), 0.02 (s, 3H), −0.03 (s, 3H); ¹³CNMR (300 MHz, CDCl₃) 146.9, 135.7, 130.8, 112.1, 81.5, 41.3, 41.0,33.43, 33.37, 26.6, 26.4, 26.2, 18.6, 18.1, 16.4, −4.3, −4.7. IR 2957,2927, 2854, 1449, 1251, 1071, 896, 867.

EXAMPLE 5 Racemic Alcohol (7a)

To the silyl ether (380 mg, 1.17 mmol) in 1 mL of THF was added 9-BBN(0.5 M in THF, 2.80 mL, 1.40 mmol) at −20° C. After 10 min the reactionmixture was warmed to room temperature and stirring was continued for 6h. TLC showed the completion of the reaction. Then 0.6 mL of 3 N NaOHwas added and this was followed by 0.6 mL of 30% H₂O₂. The resultingmixture was stirred for 12 hours at room temperature and then pouredinto 20 mL of ether and 5 mL of saturated aqueous sodium chloride. Theaqueous phase was extracted with ether and the organic solutions werecombined, dried over MgSO₄, and concentrated. Chromatography (HE:EA=10:1) gave a colorless oil (340 mg, 85%). ¹H NMR (300 MHz, CDCl₃)5.36, (m, 2H), 3.72 (dd, J=11.0, 3.8 Hz, 1H), 3.52 (dd, J=11.0, 5.7 Hz,1H), 3.49 (dd, J=3.9, 6.1 Hz), 2.42-2.30 (m, 2H), 1.76-1.58 (m, 4H),1.32-1.02 (m, 6H), 1.00 (d, J=7.1 Hz, 3H), 0.92 (s, 9H), 0.11 (s, 3H),0.09 (s, 3H). ¹³C NMR (300 MHz, CDCl₃) 136.9, 130.3, 81.9, 65.9, 42.3,41.1, 37.5, 33.37, 33.35, 26.5, 26.4, 18.5, 17.2, 16.7, −3.6, −3.7. IR3398 (broad), 2957, 2927, 1254, 1074, 1024.

EXAMPLE 6 Racemic Aldehyde (8a)

To a stirred mixture of racemic alcohol (7a) (177 mg, 0.52 mmol) andpowdered molecular sieves 4A (518 mg) in 10 mL of methylene chloride wasadded 182 mg (1.55 mmol) 4-methylmorpholine N-oxide (NMO) followed by12.7 mg, 36.2 μmmol tetrapropylammonium perruthenate (TPAP). Afterstirring at room temperature for 20 minutes, the mixture was filteredthrough a silica gel column (HE: EA=10:1) gave aldehyde 8a (170 mg, 96%)as a colorless oil. ¹H NMR (300 MHz, CDCl₃) 9.69 (d, J=1.9 Hz, 1H), 5.39(dd, J=15.4, 6.0 Hz, 1H), 5.16 (ddd, J=15.4, 8.0, 1.1 Hz), 3.75 (dd,J=6.9, 3.3 Hz, 1H), 2.51 (m, 1H), 2.37 (m, 1H), 1.87 (m, 1H), 1.73-1.60(m, 4H), 1.32-1.02 (m, 6H), 1.11 (d, J=6.9 Hz, 3H), 0.99 (d, J=6.9 Hz,3H), 0.88 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); ¹³C NMR (300 MHz, CDCl₃)204.8, 138.5, 129.3, 78.8, 50.7, 41.9, 41.0, 33.0, 32.9, 26.5, 26.3,26.2, 18.5, 17.6, 11.4, −3.8, −4.1. IR 2956, 2928, 2854, 1724, 1255,1079, 1038, 852.

EXAMPLE 7 Racemic Acetylene (9a)

To a cooled (−78° C.) solution of potassium tert-butoxide (1.0 M in THF,600 μL, 0.60 mmol) was added dimethyl diazomethylphosphonate (150 mg,1.0 mmol) in 1 mL of THF via cannula. After stirring for 10 min, asolution of racemic aldehyde (8) (170 mg, 0.50 mmol) in 2 mL of THF wasadded via cannula. The reaction was stirred at −50° C. for 20 h and then1 h at ambient temperature for 1 h. The reaction volume was reduced toapproximately 1 mL and directly chromatographed (HE: EA=50:1) to affordacetylene 9 (117.6 mg, 70%) as colorless oil. ¹H NMR (300 MHz, CDCl₃)5.39 (dd, J=15.4, 5.8 Hz, 1H), 5.27 (dd, J=15.6, 7.6 Hz, 1H), 3.37 (dd,J=6.7, 3.6 Hz, 1H), 2.65 (m, 1H), 2.39 (m, 1H), 2.02 (dd, J=2.4, 0.80Hz), 1.92 (m, 1H), 1.74-1.60(m, 4H), 1.32-1.02 (m, 6H), 1.17 (d, J=7.1Hz, 3H), 0.97 (d, J=6.9 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.06 (s,3H). ¹³C NMR (300 MHz, CDCl₃) 136.3, 131.2, 87.2, 79.1, 70.3, 41.7,41.0, 33.3, 33.2, 31.7, 26.6, 26.41, 26.39, 18.7, 17.9, 17.4, −3.4,−3.6. IR 3312, 2957, 2927, 2854, 1253, 1080, 860.

EXAMPLE 8 Racemic Aldehyde (10a)

A solution of Sudan red 7B (1 mg/mL, 20 μL) was added to a solution ofracemic acetylene (9a) (52.5 mg, 0.15 mmol in 4 mL of methylenechloride). The solution was cooled to −78° C. and flushed with argon for5 min. A flow of ozone was passed through the solution until the pinkcolor disappeared (ca, 5 min). The remaining ozone was then purged withargon for 10 min, and then 1 mL of dimethyl sulfide was added. Afterstirring for 1 h at −78° C. and then 2 h at ambient temperature, thesolution was concentrated in vacuo. Chromatography (HE: EA=40:1) gave acolorless oil (28.8 mg, 75%). ¹H NMR (300 MHz, CDCl₃) 9.89 (d, J=0.90Hz, 1H), 4.08 (m, 1H), 2.76-2.60 (m, 2H), 2.10 (d, J=2.7 Hz, 1H), 1.22(d, J=7.1 Hz, 3H), 1.12 (d, J=7.1 Hz, 3H), 0.90 (s, 9H), 0.11 (s, 3H),0.06 (s, 3H). IR 3312, 2957, 2927, 2854, 1253, 1080, 860.

The Chiral Series (Scheme 1)

EXAMPLE 9 (S)-Allylic Alcohol (3)

To lithium powder (562 mg, 81 mmol) under argon was added dry ether (50mL). The suspension was cooled to −35° C. With stirring, a solution of(Z)-1-bromo-propene (4.84 g, 40 mmol) was added dropwise. The resultingmixture was stirred at −35° C. for 2 h and then treated dropwise withzinc bromide solution (0.6 M in ether, 77 mL, 44 mmol). The reactionmixture was stirred for an additional 1 h at 0° C. and then a solutionof lithium (1R, 2S)-N-methylephedrate, prepared by the addition ofn-butyllithium (2.5M in hexanes, 16.4 mL, 41 mmol) to a solution of(−)—N-methylephedrine (7.35 g, 41 mmol) in toluene (100 mL) at 0° C.,was added by cannula. The solution was stirred for 1 h at 0° C. and thencyclohexanecarboxaldehyde (3.20 g, 28.6 mmol) was added neat. Afterstirring for 1 h at 0° C., the reaction was quenched by the addition ofsaturated aqueous ammonium chloride solution. The organic phase wasseparated and the aqueous phase was extracted with ether. The combinedorganic solution was washed with a second portion of ammonium chloridesolution, dried over MgSO₄, and concentrated. Chromatography (HE:EA=10:1) gave alcohol (S)-3 (3.61 g, 82%, 92% ee. according to NMR studyof Mosher ester) as a clear liquid. ¹H NMR (300 MHz, CDCl₃) 5.57 (dqd,J=10.2, 6.8, 1.3 Hz, 1H), 5.36 (ddq, J=10.2, 9.4, 1.8 Hz, 1H), 4.14 (dd,J=8.4 Hz, 1.0 Hz, 1H), 1.90 (m, 1H), 1.80-1.58 (m, 8H), 1.58-0.80 (m,6H); ¹³C NMR (300 MHz, CDCl₃) 132.4, 126.9, 71.7, 44.3, 29.0, 28.6,26.8, 26.3, 26.2, 13.7. IR 3365 (broad), 2923, 28523, 1449, 1022, 994.

EXAMPLE 10 (S)-Ether (4)

A 100-mL reaction flask was charged with 95% sodium hydride (3.49 g, 146mmol) and 30 mL of dry THF. Chiral alcohol 3 (3.20 g, 20.8 mmol) in 3 mLof THF was added dropwise followed by 3-chloro-2-methylpropene (5.65 g,62.4 mmol). The reaction mixture was stirred at reflux overnight andthen cooled to room temperature. Excess sodium hydride was quenched bythe slow addition of 5 mL of water. The resulting mixture was pouredinto water. Ether extracts (50 mL×3) were combined and the resultingorganic solution was dried over MgSO₄, filtered, and concentrated.Chromatography (HE: EA=30:1) produced a colorless oil (3.68 g, 85%). ¹HNMR (300 MHz, CDCl₃) 5.73 (dqd, J=10.2, 6.8, 1.3 Hz, 1H), 5.24 (ddq,10.2, 9.4, 1.8 Hz, 1H), 4.93 (m, 1H), 4.85 (m, 1H), 3.90 (d, J=12.6 Hz,1H), 3.80 (m, 1H), 3.69 (d, J=12.4 Hz, 1H), 1.96 (m, 1H), 1.73 (s, 3H),1.70-1.65 (m, 5H), 1.62 (dd, J=7.1, 2.0 Hz, 3H), 1.58-0.80 (m, 6H); ¹³CNMR (300 MHz, CDCl₃) 143.3, 130.9, 128.1, 112.1, 77.9, 72.0, 43.1, 31.9,29.7, 28.9, 27.0, 26.5, 26.4, 23.0, 20.0, 14.4, 13.9. IR 2971, 2922,2852, 1449, 1085, 896.

EXAMPLE 11 Chiral Dienol (5)

Potassium tert-butoxide (1.0 M in THF, 17.5 mL, 17.5 mmol) was added toa flask under argon and an additional 15.0 mL of THF was added. Thesolution was cooled to −78° C. and chiral ether 4 (16.0 mmol, 3.35 g)was added. n-Butyllithium (1.6M in THF, 12.1 mL, 19.3 mmol) was slowlyadded. The mixture was warmed to −20° C. over 4 h and the stirred 12 hat −20° C. and 2 h at 0° C. The reaction was quenched with water and theresulting mixture was extracted with ether. The organic phase was driedover MgSO₄ and concentrated. Chromatography (HE: EA=10:1) gave acolorless oil (2.68 g, 80%). ¹H NMR (300 MHz, CDCl₃) 5.40 (dd, J=16.2,6.6 Hz, 1H), 5.31 (dd, J=16.2, 6.6 Hz, 1H), 4.92 (m, 1H), 4.86 (m, 1H),3.87 (d, J=20.0 Hz, 1H), 2.33 (m, 1H), 1.90 (m, 1H), 1.69 (s, 3H),1.68-1.65 (m, 5H), 1.32-1.05 (m, 6H), 0.97 (d, J=6.9 Hz, 3H); ¹³C NMR(300 MHz, CDCl₃) 146.2, 137.4, 129.9, 112.1, 79.3, 41.0, 40.1, 33.5,33.4, 26.5, 26.4, 18.9, 14.8. IR 3403 (broad), 2965, 2924, 2851, 1448,979, 968, 896.

EXAMPLE 12 Chiral Silyl Ether (6a)

A mixture of chiral dienol 5 (1.27 g, 6.13 mmol) and 2,6-lutidine (1.15g, 1.25 mL, 10.7 mmol) in 20 mL of methylene chloride was cooled to −20°C. t-BuMe₂SiOTf where Tf=triflate (1.86 g, 1.62 L, 7.05 mmol) was addedover 5 min. The mixture was stirred for 1 hour at −20° C. and 30 min atroom temperature. The mixture was diluted with 40 mL of ether and pouredinto 25 mL of 1 M NaHSO₄ solution. The resulting layers were separatedand water phase was extracted with ether. The combined organic solutionwas washed with 1 M NaHSO₄ solution, sodium bicarbonate and brine. Thesolution was then dried over MgSO₄, filtered, and concentrated.Chromatography (HE: EA=30:1) gave a colorless oil (1.83 g, 92%). ¹H NMR(300 MHz, CDCl₃) 5.30 (dd, J=16.1, 6.6 Hz, 1H), 5.19 (dd, J=16.1, 6.6Hz, 1H), 4.78 (m, 1H), 4.75 (m, 1H), 3.71 (d, J=7.0 Hz, 1H), 2.17 (m,1H), 1.88 (m, 1H), 1.75-1.64 (m, 4H), 1.63 (s, 3H), 1.32-0.96 (m, 6H),0.94 (d, J=7.0 Hz, 3H), 0.89 (s, 9H), 0.02 (s, 3H), −0.03 (s, 3H); ¹³CNMR (300 MHz, CDCl₃) 146.9, 135.7, 130.8, 112.1, 81.5, 41.3, 41.0,33.43, 33.37, 26.6, 26.4, 26.2, 18.6, 18.1, 16.4, −4.3, −4.7. IR 2957,2927, 2854, 1449, 1251, 1071, 896, 867.

EXAMPLE 13 Chiral MOM Ether (6b)

MOMCl (567 mg, 535 μL, 7.05 mmol) was added via syringe dropwise to asolution of chiral alcohol 5 (296 mg, 1.41 mmol) in 8 mL of methylenechloride at 0° C., followed by addition of ^(i)Pr₂NEt (911 mg, 1.23 mL,7.05 mmol). The resulting mixture was stirred at 0° C. for 2 h and thenat ambient temperature for 16 h. Saturated solution of sodium carbonate(4 mL) was added to quench the reaction. The aqueous phase was extractedwith methylene chloride (25 mL×3) and the organic phases were combined,dried (MgSO₄), and concentrated. Chromatography (HE: EA=10:1) gavechiral MOM ether 6b as a colorless oil (323 mg, 90%). ¹H NMR (300 MHz,CDCl₃) δ 5.35 (dd, J=15.6, 6.6 Hz, 1H), 5.17 (dd, J=12.6, 7.8 Hz, 1H),4.91 (d, J=0.9 Hz, 1H), 4.84 (s, 1H), 4.61 (m, 1H), 4.47 (d, J=6.6 Hz,1H), 3.67 (d, J=7.2 Hz, 1H), 3.37 (s, 1H), 2.27 (m, 1H), 1.86 (m, 1H),1.75-1.45 (m, 7H), 0.90-1.30(m, 9H); ¹³C NMR (300 MHz, CDCl₃) δ 143.2,136.2, 129.8, 115.3, 93.9, 84.7, 55.9, 40.9, 39.5, 33.4, 26.5, 26.3,17.6, 17.4; IR (neat) ν_(max) 2923, 2851, 1450, 1153, 1095, 1033, 968.

EXAMPLE 14 Chiral Alcohol (7a)

To the chiral silyl ether 6a (1.57 g, 4.84 mmol) in 5 mL of THF wasadded 9-BBN (0.5 M in THF, 11.6 mL, 5.80 mmol) at −20° C. After 10 minthe reaction mixture was warmed to room temperature and stirring wascontinued for 6 hours. TLC showed the completion of the reaction. Then 3mL of 3 N NaOH was added and this was followed by 3 mL of 30% H₂O₂. Theresulting mixture was stirred for 12 hours at room temperature and thenpoured into 100 mL of ether and 20 mL of saturated aqueous sodiumchloride. The aqueous phase was extracted with ether and the organicsolutions were combined, dried over MgSO₄, and concentrated.Chromatography (HE: EA=10:1) gave a colorless oil (1.43 g, 86%). ¹H NMR(300 MHz, CDCl₃) 5.36, (m, 2H), 3.72 (dd, J=11.0, 3.8 Hz, 1H), 3.52 (dd,J=11.0, 5.7 Hz, 1H), 3.49 (dd, J=3.9, 6.1 Hz), 2.42-2.30 (m, 2H),1.76-1.58 (m, 4H), 1.32-1.02 (m, 6H), 1.00 (d, J=7.1 Hz, 3H), 0.92 (s,9H), 0.11 (s, 3H), 0.09 (s, 3H). ¹³C NMR (300 MHz, CDCl₃) 136.9, 130.3,81.9, 65.9, 42.3, 41.1, 37.5, 33.37, 33.35, 26.5, 26.4, 18.5, 17.2,16.7, −3.6, −3.7. IR 3398 (broad), 2957, 2927, 1254, 1074, 1024.

EXAMPLE 15 Chiral Alcohol (7b)

Chiral alcohol 7b was prepared by the procedure above from chiral olefin6b. ¹H NMR (400 MHz, CDCl₃) δ 5.36 (m, 2H), 4.65 (d, J=6.6 Hz, 1H), 4.59(d, J=6.6 Hz, 1H), 3.82, (m, 1H), 3.49 (m, 1H), 3.41 (s, 3H), 3.34 (dd,J=7.5, 4.2 Hz, 1H), 2.82 (dd, J=7.3, 5.7 Hz, 1H), 2.37 (m, 1H),1.95-1.80 (m, 2H), 1.78-1.60 (m, 5H), 1.32-1.00 (m, 4H), 0.98 (d, J=3.7Hz, 3H), 0.97 (d, J=3.7 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ 136.5,131.0, 99.0, 87.1, 65.4, 56.5, 40.9, 39.3, 37.4, 33.33, 33.27, 26.4,26.3, 15.3, 14.5; IR (neat) ν_(max) 3420(broad), 2922, 2850, 1449, 1147,1095, 1032.

EXAMPLE 16 Chiral Aldehyde (8a)

To a stirred mixture of chiral alcohol 7a (220 mg, 0.64 mmol) andpowdered molecular sieves 4A (600 mg) in 10 mL of methylene chloride wasadded 4-methylmorpholine N-oxide (NMO) (226 mg, 1.93 mmol) followed bytetrapropylammonium perruthenate (TPAP) (15.8 mg, 44.9 μmmol). Afterstirring at room temperature for 30 min, the mixture was filteredthrough a silica gel column (HE: EA=10:1), which gave chiral aldehyde 8a(215 mg, 98%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) 9.69 (d, J=1.9Hz, 1H), 5.39 (dd, J=15.4, 6.0 Hz, 1H), 5.16 (ddd, J=15.4, 8.0, 1.1 Hz),3.75 (dd, J=6.9, 3.3 Hz, 1H), 2.51 (m, 1H), 2.37 (m, 1H), 1.87 (m, 1H),1.73-1.60 (m, 4H), 1.32-1.02 (m, 6H), 1.11 (d, J=6.9 Hz, 3H), 0.99 (d,J=6.9 Hz, 3H), 0.88 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); ¹³C NMR (300MHz, CDCl₃) 204.8, 138.5, 129.3, 78.8, 50.7, 41.9, 41.0, 33.0, 32.9,26.5, 26.3, 26.2, 18.5, 17.6, 11.4, −3.8, −4.1. IR 2956, 2928, 2854,1724, 1255, 1079, 1038, 852.

EXAMPLE 17 Chiral Aldehyde (8b)

Chiral aldehyde 8b was prepared by the same procedure applied to chiralalcohol 7b. ¹H NMR (400 MHz, CDCl₃) δ 9.68 (d, J=1.8 Hz, 1H), 5.40 (dd,J=15.6, 6.6 Hz, 1H), 5.16 (ddd, J=15.6, 8.2, 1.3 Hz), 4.66 (d, J=7.1 Hz,1H), 4.64 (d, J=7.0 Hz, 1H), 3.63 (dd, J=7.0, 4.4 Hz, 1H), 3.35 (s, 3H),2.64 (m, 1H), 2.40 (m, 1H), 1.86 (m, 1H), 1.72-1.55 (m, 4H), 1.32-1.02(m, 6H), 1.11 (d, J=7.1 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H); ¹³C NMR (300MHz, CDCl₃) δ 203.9, 138.5, 129.3, 97.7, 84.2, 56.3, 49.3, 40.9, 39.9,33.01, 32.98, 26.4, 26.3, 16.8, 11.0; IR (neat) ν_(max) 2926, 2853,1724, 1147, 1099, 1033.

EXAMPLE 18 Chiral Acetylene (9a)

To a cooled (−78° C.) solution of dimethyl 1-diazophosphonoacetone(Ohira-Bestmann's reagent, 916 mg, 4.17 mmol) in 30 mL of THF was addedsodium methoxide (0.5 M in THF, 9.54 mL, 4.77 mmol) dropwise viacannula. After stirring for 15 min, a solution of chiral aldehyde 8a(540 mg, 1.59 mmol) in 10 mL of THF was added via cannula. The reactionmixture was slowly warmed to room temperature over 1 hour and quenchedwith saturated aqueous ammonium chloride solution (10 mL). The mixturewas then diluted with water (45 mL) and then extracted with ether (3×45mL). The combined extracts were washed with brine, dried over sodiumsulfate and concentrated. Chromatographed (HE: EA=50:1) afforded chiralacetylene 9a (480 mg, 90%) as colorless oil. ¹H NMR (300 MHz, CDCl₃)5.39 (dd, J=15.4, 5.8 Hz, 1H), 5.27 (dd, J=15.6, 7.6 Hz, 1H), 3.37 (dd,J=6.7, 3.6 Hz, 1H), 2.65 (m, 1H), 2.39 (m, 1H), 2.02 (dd, J=2.4, 0.80Hz), 1.92 (m, 1H), 1.74-1.60(m, 4H), 1.32-1.02 (m, 6H), 1.17 (d, J=7.1Hz, 3H), 0.97 (d, J=6.9 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.06 (s,3H). ¹³C NMR (300 MHz, CDCl₃) 136.3, 131.2, 87.2, 79.1, 70.3, 41.7,41.0, 33.3, 33.2, 31.7, 26.6, 26.41, 26.39, 18.7, 17.9, 17.4, −3.4,−3.6. IR 3312, 2957, 2927, 2854, 1253, 1080, 860.

EXAMPLE 19 Chiral MOM-Protected Acetylene (9b)

To a cooled (−78° C.) solution of dimethyl 1-diazophosphonoacetone(Ohira-Bestmann's reagent, 461 mg, 2.40 mmol) in 10 mL of THF was addedsodium methoxide (0.5 M in THF, 4.80 mL, 2.40 mmol) dropwise viacannula. After stirring for 15 min, a solution of chiral aldehyde 8b(160 mg, 0.60 mmol) in 3 mL of THF was added via cannula. The reactionmixture was allowed to slowly warmed to room temperature over 1 h andquenched with saturated aqueous ammonium chloride solution (3 mL). Themixture was then diluted with water (15 mL) and then extracted withether (3×15 mL). The combined extracts were washed with brine, driedover sodium sulfate and concentrated. Chromatographed (HE: EA=10:1)afforded chiral acetylene 9b (136 mg, 85%) as colorless oil. ¹H NMR (400MHz, CDCl₃) δ 5.46 (dd, J=15.4, 6.6 Hz, 1H), 5.24 (ddd, J=15.4, 8.2, 1.2Hz), 4.74 (d, J=7.0 Hz, 1H), 4.70 (d, J=7.0 Hz, 1H), 3.42 (s, 3H), 3.14,(dd, J=7.9, 3.5 Hz, 1H), 2.76 (m, 1H), 2.49 (m, 1H), 2.07 (d, J=2.6 Hz,1H), 1.96-1.84 (m, 1H), 1.72-1.58 (m, 5H), 1.23 (d, J=6.7 Hz, 3H),1.18-1.07 (m, 5H), 1.04 (d, J=6.8 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ137.2, 130.1, 98.5, 86.3, 85.9, 70.1, 70.0, 56.5, 41.0, 40.9, 33.2,33.1, 29.9, 26.4, 26.3, 18.6, 17.2; IR (neat) ν_(max) 2926, 2.851, 1149,1096, 1035.

EXAMPLE 20 Chiral Aldehyde (10a)

A solution of Sudan red 7B (1 mg/mL, 100 μL) was added to a solution ofchiral acetylene 9a (153 mg, 0.455 mmol) in 4 mL of methylene chloride.The solution was cooled to −78° C. and flushed with argon for 5 min. Aflow of ozone was passed through the solution until the pink colordisappeared (ca, 5 min). The remaining ozone was then purged with argonfor 10 min, and then triphenyl phosphine (119 mg, 0.455 mmol) was added.After stirring for 1 h at −78° C. and then 6 hours at ambienttemperature, the solution was concentrated in vacuo. Chromatography (HE:EA=40:1) gave a colorless oil (101 mg, 86%). ¹H NMR (300 MHz, CDCl₃)9.89 (d, J=0.90 Hz, 1H), 4.08 (m, 1H), 2.76-2.60 (m, 2H), 2.10 (d, J=2.7Hz, 1H), 1.22 (d, J=7.1 Hz, 3H), 1.12 (d, J=7.1 Hz, 3H), 0.90 (s, 9H),0.11 (s, 3H), 0.06 (s, 3H). ¹³C NMR (300 MHz, CDCl₃) 204.3, 74.1, 72.1,50.8, 31.4, 26.1, 18.5, 17.3, 9.8, −4.0, −4.1. IR 3312, 2955, 2932,2886, 1711, 1463, 1120, 837, 776.

EXAMPLE 21 Chiral Aldehyde (10b)

A solution of Sudan red 7B (1 mg/mL, 100 μL) is added to a solution ofacetylene 9b in methylene chloride. The solution is cooled to −78° C.and flushed with argon for 5 min. A flow of ozone is passed through thesolution until the pink color disappears (ca, 5 min). The remainingozone is then purged with argon for 10 min, and then triphenyl phosphineis added. After stirring for 1 h at −78° C. and then 6 hours at ambienttemperature, the solution is concentrated in vacuo. Chromatography (HE:EA=40:1) gives aldehyde 10b.

EXAMPLE 22 Chiral Vinyl Iodide (1d)

A suspension of ethyl triphenyl phosphine iodide (4.57 g, 10.9 mmol) in45 mL of THF at room temperature was treated with n-BuLi (2.5 M inhexanes, 4.44 mL, 11.1 mmol). After 10 min, all solid disappeared. Theresulting red transparent solution was added to a cold solution (−78°C.) of iodine (2.64 g, 10.4 mmol in 70 mL of THF). After 10 min at −78°C., the reaction mixture was warmed to room temperature over 2 hours.The yellow slurry was filtered and washed with hexanes to give 6.0 gsolid.

To a suspension of the solid prepared above (385 mg, 0.708 mmol) in 3 mLof THF at −25° C., sodium hexamethyldisilazane (NaHMDS) (1.0 M in THF,0.708 mL, 0.708 mmol) was added dropwise. After 15 min, the resultingred solution was cooled to −35° C. Aldehyde 10 (80 mg, 0.315 mmol) in 1mL of THF was added dropwise. The reaction mixture was stirred for 45min at −35° C. and then warmed to room temperature over 2 hours. Thereaction was then quenched with methanol (0.5 mL) and concentrated. Theresidue was filtered through a silica column (50% ethyl acetate inhexanes) and purified by chromatography (HE: EA=50:1) to give chiralvinyl iodide 1d as colorless oil (49 mg, 41%). ¹HNMR (300 MHz, CDCl₃)5.41 (dq, J=8.9, 1.4 Hz, 1H), 3.61 (dd, J=5.8, 4.7 Hz, 1H), 2.70-2.58(m, 2H), 2.47 (d, J=1.4 Hz, 3H), 2.07 (d, J=2.5 Hz, 1H), 1.21 (d, J=7.1Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.92 (s, 9H), 0.09 (s, 3H), 0.05 (s,3H). ¹³C NMR (300 MHz, CDCl₃) 139.2, 99.7, 87.3, 77.5, 70.6, 45.4, 33.9,32.1, 26.3, 18.6, 17.3, 15.2, −3.6, −3.7. IR 3311, 2894, 2885, 2856,1471, 1461, 1252, 1112.

EXAMPLE 23 Chiral Vinyl Iodide (1e)

To a suspension of the iodinated Wittig reagent prepared as above in THFat −25° C., sodium hexamethyldisilazane (NaHMDS, 1 equiv) is addeddropwise. After 15 min, the resulting red solution is cooled to −35° C.Aldehyde 10 (0.5 equiv) in 1 mL of THF is added dropwise. The reactionmixture is stirred for 45 min at −35° C. and then warmed to roomtemperature over 2 hours. Quenching with methanol and concentrationgives a residue that is filtered through a silica column (50% ethylacetate in hexanes) and purified by chromatography to give chiral vinyliodide 1e.

Synthesis of Aldehyde 13 (Scheme 2)

EXAMPLE 24 Chiral Alcohol (11)

To the solution of (−)-B-methoxydiisopinocampheylborane (215 mg, 0.680mmol) in 5 mL of ether was added allyl magnesium bromide (1.0 M inether, 649 μL, 649 mmol) dropwise at room temperature. After 1 h at roomtemperature, the reaction mixture was cooled to −78° C. Chiral aldehyde8a (210 mg, 0.618 mmol) in 2 mL of ether was added dropwise. After beingstirred for 5 h at −78° C. and 5 h at −40° C., the reaction was added 1mL of 3N NaOH and 1 mL of 30% H₂O₂ and warmed to room temperature. Themixture was refluxed 2 h and then poured into brine (10 mL). The aqueousphase was extracted with ether and the organic phase was combined, dried(MgSO₄), and concentrated. Chromatography (HE: CH₂Cl₂=1:1) first gavechiral alcohol 11 (168 mg, 71%) as a colorless oil and then the 4Risomer (40.1 mg, 17%) as a colorless oil.

For chiral alcohol 11: ¹H NMR (300 MHz, CDCl₃) δ 5.90 (m, 1H), 5.30 (m,2H), 5.11 (m, 1H), 5.07 (d, J=1.5 Hz, 1H), 3.64 (tt, J=8.5, 2.7 Hz, 1H),3.53 (dd, J=6.0, 4.6 Hz, 1H), 2.93 (d, J=2.5 Hz, 1H), 2.42-2.28 (m, 2H),2.14-2.02 (m, 1H), 1.98-1.60 (m, 7H), 1.38-1.01, (m, 5H), 0.97 (d, J=6.9Hz, 1H), 0.92 (s, 9H), 0.85 (d, J=6.9 Hz, 1H), 0.09 (s, 3H), 0.08 (s,3H). ¹³C NMR (300 MHz, CDCl₃) δ 137.0, 135.8, 131.0, 117.3, 80.9, 72.8,42.8, 42.1, 41.0, 39.0, 33.41, 33.34, 26.5, 26.38, 26.35, 18.5, 17.1,15.3, −3.7, −3.8; IR (neat) ν_(max) 3500 (broad), 2926, 2854, 1462,1449, 1254, 1003, 974, 835. For the 4R isomer of chiral alcohol 11. ¹HNMR (300 MHz, CDCl₃) δ 5.76 (m, 1H), 5.31 (m, 2H), 5.12-4.98 (m, 2H),4.20 (t, J=6.7 Hz, 1H), 3.52 (dd, J=7.7, 2.2 Hz, 1H), 3.45 (s, 1H), 2.47(m, 1H), 2.28 (m, 1H), 2.03 (m, 1H), 1.98-1.60 (m, 7H), 1.38-1.01, (m,5H), 1.01 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.92 (s, 9H), 0.13(s, 3H), 0.11 (s, 3H). ¹³C NMR (300 MHz, CDCl₃) δ 136.8, 135.9, 130.1,116.9, 83.8, 70.5, 42.0, 41.1, 39.6, 37.2, 33.38, 33.32, 26.5, 26.4,18.6, 12.3, −3.3, −3.6; IR (neat) ν_(max) 3505 (broad), 2926, 2854,1462, 1449, 1255, 1084, 1019, 1003.

EXAMPLE 25 Chiral Aldehyde (12)

To chiral alcohol 11 (191 mg, 0.50 mmol) in 15 mL of CH₂Cl₂ at −78° C.,03 was flushed in until the solution turned into blue. After thesolution being flushed with argon for 10 min at −78° C., Ph₃P (327 mg,1.25 mmol) was added. After 1 h at −78° C. and 6 h at room temperature,the mixture was concentrated. Chromatography (HE: EA=5:1) gave chiralcompound 12 as a colorless oil (125 mg, 91%). ¹H NMR (300 MHz, CDCl₃) δ9.82 (m, 1H), 5.48 (d, J=10.7 Hz, 0.5H), 5.22 (s, 0.5H), 4.83 (d,J=10.4, 0.5H), 4.38 (m, 0.5H), 4.08 (m, 0.5H), 3.74 (s, 0.5H), 3.66 (t,J=2.5 Hz, 0.5H), 2.65-2.40 (m, 2H), 2.10-1.62 (m, 2H), 1.03-0.79 (m,15H), 0.14 (s, 1.5H), 0.10 (s, 1.5H), 0.06 (s, 1.5H), 0.04 (s, 1.5H); IR(neat) ν_(max) 3450 (broad), 2962, 2930, 1724, 1708, 1172, 1154, 1109,1095.

EXAMPLE 26 Acetal (13)

To a solution of chiral compound 12 (120 mg, 0.438 mmol) in 1 mL ofCH₂Cl₂ was added imidazole (44.7 mg, 0.657 mmol), DMAP (13.4 mg, 0.11mmol), TBDMSCl(198 mg, 1.31 mmol) at 0° C. The mixture was stirred for12 h and then directly loaded on silica gel column. Chromatography (HE:EA=10:1) gave compound 13 as a colorless oil (128 mg, 70%). ¹H NMR (300MHz, CDCl₃) δ 9.82 (t, J=2.7 Hz, 1H), 5.21 (d, J=3.0 Hz, 1H), 4.05 (dt,J=10.2, 6.3 Hz, 1H), 3.66 (t, J=2.7 Hz, 1H), 2.49 (m, 2H), 1.88-1.77 (m,1H), 1.76-1.64 (m, 1H), 0.94 (d, J=7.2 Hz, 3H), 0.92 (s, 9H), 0.88 (s,9H), 0.80 (d, J=7.0 Hz, 3H), 0.07 (s, 3H), 0.06 (s, 6H), 0.05 (s, 3H);¹³C NMR (300 MHz, CDCl₃) δ 202.5, 94.6, 76.6, 72.2, 46.9, 43.0, 34.8,26.1, 26.0, 18.3, 13.8, 9.60, −3.9, −4.3, −4.7, −5.1; IR (neat) ν_(max)2955, 2928, 1731, 1462, 1174, 1120, 1049, 836.

Synthesis of (+)-Discodermolide (Scheme 3)

EXAMPLE 27 Alcohol (14)

To a cold solution (−78° C.) of alkyne 1e is added dropwise 1 equivalentof LDA in cyclohexane. The mixture is stirred at −78° C. over 1 h.Aldehyde 13 is added dropwise in THF. The temperature is increased to−40° C. and stirred for 1 h. Water is added dropwise at −40° C. and themixture is warmed to room temperature. The aqueous phase is extractedwith ether and organic phases are combined, dried (Na₂SO₄).Chromatography (HE: EA=mixtures) gives compound 14.

EXAMPLE 28 MOM Ether (15)

To a solution of alcohol 14 in methylene chloride at 0° C. is addedMOMCl (approx 4 equiv), ^(i)Pr₂NEt (approx 8 equiv) and DMAP (approx 4equiv). The reaction is stirred for 2 h at 0° C. and then 16 h at roomtemperature. A saturated solution of sodium carbonate is added to quenchthe reaction. The aqueous phase is extracted with methylene chloride andthe organic phases are combined, dried (MgSO₄), and concentrated.Chromatography (HE: EA mixtures) gives the MOM ether 15.

EXAMPLE 29 Suzuki Product (17)

A 1.0 M solution of anhydrous ZnCl₂ (1.2 equiv) is added to a solutionof iodide 16 (1.2 equiv) in ether and the resulting solution is thencooled to −78° C. Then t-BuLi (1.0 equiv) is added dropwise. Theresulting solution is stirred for 5 min and then warmed to roomtemperature. After stirring for 1 h, the resulting suspension istransferred by cannula into a mixture of vinyl iodide 15 (1.0 equiv) andPd(PPh₃)₄ (0.12 equiv). The reaction mixture is stirred overnight in theabsence of light and quenched with water. The mixture is diluted etherand the layers are separated. The water layer is extracted and thecombined organic layers are washed with saturated aqueous NaHCO₃ andbrine, dried (MgSO₄), filtered and concentrated. Chromatography (HE: EAmixtures) gives compound 17.

EXAMPLE 30 Diene (18)

To a solution of compound 17 in 5 mL of hexanes is added Lindlarcatalyst (Pd/CaCO₃ poisoned with Pb, 5% Pd, 50 mg) and quinoline (5 μL).H₂ is bubbled through the reaction mixture for 20 min and the resultantsuspension is stirred vigorously for 24 h under a balloon atmosphere ofH₂. After filtration through Celite with ether, the solution isconcentrated. Chromatography (HE: EA mixtures) gives compound 18.

EXAMPLE 31 Alcohol (19)

To a solution of compound 18 (1 equiv) in CH₂Cl₂ is added DIBAL (3equiv) at 0° C. The resulting solution is stirred for 5 h and quenchedwith pH 7.0 buffer (0.1 mL), then diluted with CH₂Cl₂ (10 mL). To themixture is then added 2 mL of saturated sodium potassium tartratesolution and it was extracted with CH₂Cl₂. The organic layer is washedwith water, dried and concentrated. Chromatography (HE: EA mixtures)gives compound 19.

EXAMPLE 32 Aldehyde (20)

To a solution of compound 19 in CH₂Cl₂ are added Dess-Martin periodinane(1.1 equiv) and NaHCO₃ (3 equiv). The resulting solution is stirred for3 h and quenched with equal volumes of saturated NaS₂O₃ solution andsaturated NaHCO₃. The mixture is then extracted with ether. The organicsolution is then washed with water, dried and concentrated. Theresulting residue is used without purification.

EXAMPLE 33 Tetraene (21)

To a −78° C. solution of freshly distilled allyldiphenylphosphine in THF(2 mL) is added t-butyllithium (1.0 equiv) and stirred for 5 min. Thesolution is warmed to 0° C., stirred for 30 min and cooled to −78° C.The solution is treated with freshly distilled Ti(Oi-Pr)₄ (1.0 equiv)and stirred for 30 min. A precooled (−78° C.) solution of aldehyde 10(0.5 equi) in THF is added via cannula and stirred for 1 h, then warmedto 0° C. Iodomethane (5 equiv) is added, and the solution is warmed toroom temperature and stirred for 16 h. The solution is quenched with pH7.0 buffer and extracted with CH₂Cl₂ and ether. The combined organiclayers are washed with brine solution, dried and concentrated.Chromatography (HE: EA=2:1) gives tetraene 21.

EXAMPLE 34 Alcohol (22)

At 0° C., a solution of 1 equivalent tetraene 21 in CH₂Cl₂ (3 mL) istreated with H₂O (50 μL) and 1.2 equivalents DDQ. The mixture is stirredfor 10 min at 0° C., warmed to rt and stirred an additional 5 min. Themixture is quenched with 0.5 mL saturated NaHCO₃, diluted with CH₂Cl₂(30 mL), and washed with water (50 mL) and saturated brine (50 mL). Thecombined organic layers are dried and concentrated. Chromatography (HE:EA=2:1) gives compound 22.

EXAMPLE 35 Urethane (23)

A solution of alcohol 22 in CH₂Cl₂ is treated with ClCCON═C═O (1.2equiv) at room temperature for 30 min. The solution is loaded directlyonto neutral Al₂O₃. After 4 h, the material is flushed from the Al₂O₃(EtOAc) and the eluent is concentrated. Chromatography (HE: EA=10:1)gives compound 23.

EXAMPLE 36 Lactol (24)

A solution of compound 23 in THF is treated with excess TBAF (1.0 M inTHF, 1 mL) at room temperature for 30 min. The organic layer isseparated and the aqueous layer is extracted with ether. The combinedorganic layer is combined, dried and concentrated. Chromatography (HE:EA=2:1) gives compound 24.

EXAMPLE 37 Lactone (25)

A solution of compound 24 in CH₂Cl₂ is added MnO₂ (3 mole equiv). Themixture is stirred for 12 h at room temperature and then concentrated.The resulting residue is loaded on silica gel. Elution gives compound25.

EXAMPLE 38 (+)-Discodermolide

To a solution of compound 25 in THF is added an aqueous solution of 4 NHCl. The mixture is stirred at room temperature for 24 h. Saturatedaqueous NaHCO₃ is added dropwise followed by EtOAc. The organic phase iswashed with brine. The aqueous phase is extracted with EtOAc, and thecombined extracts are dried and concentrated. Chromatography (HE:EA=2:1) gives a white solid.

Thus, whereas there have been described what are presently believed tobe the preferred embodiments of the present invention, those skilled inthe art will realize that other and further embodiments can be madewithout departing from the spirit of the invention, and it is intendedto include all such further modifications and changes as come within thetrue scope of the claims set forth herein.

1. A compound having the formula:

wherein R′ is H or a protecting group, and R2 and R3 each independentlyrepresent H, methyl, or a leaving group, provided that at least one ofR2 and R3 is a leaving group.
 2. A compound according to claim 1,wherein only one of R2 and R3 is a leaving group.
 3. A compoundaccording to claim 1, wherein R′ is a protecting group.
 4. A compoundaccording to claim 3, wherein the protecting group is a member of thesilyl class of protecting groups.
 5. A compound according to claim 4,wherein the protecting group has the formula:—Si(O_(x)R⁴)(O_(y)R⁵)(O_(z)R^(6a))  (2) wherein x, y, and zindependently represent 0 or 1; and R4, R5 and R˜˜ each independentlyrepresent a linear or branched alkyl group having one to four carbonatoms, any two of the alkyl groups optionally being connected to form asilicon-containing ring; or an aryl group selected from the groupconsisting of phenyl, pyridinyl, pyrrolyl, and furanyl.
 6. A compoundaccording to claim 5, wherein x, y, and z are all 0, and the silyl groupis selected from triethylsilyl, tri-(n-propyl)silyl, triisopropylsilyl,tri-(n-butyl)silyl, triisobutylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, phenyldimethylsilyl, methyldiphenylsilyl, ortriphenylsilyl.
 7. A compound according to claim 5, wherein at least oneof x, y, and z is 1, and the silyl group is selected fromtrimethoxysilyl, dimethoxymethylsilyl, methoxydimethylsilyl,ethoxydimethylsilyl, methoxydiethylsilyl, isopropoxydimethylsilyl,phenoxydimethylsilyl, phenoxydiethylsilyl, methyldiphenoxysilyl,[2,4,6-tri-(t-butyl)phenoxy]dimethylsilyl, t-butoxydimethylsilyl,tbutoxydiphenylsilyl, (t-butyl)(methoxy)phenylsilyl, andmethoxydiphenylsilyl.
 8. A compound according to claim 4, wherein theprotecting group is tbutyldimethylsilyl.
 9. A compound according toclaim 3, wherein the protecting group is a member of the acetallketalclass of protecting groups.
 10. A compound according to claim 9, whereinthe protecting group has the formula:

wherein: R˜ represents an alkyl group optionally substituted with anaryl group; R7 represents hydrogen, an alkyl group, or an aryl group;and R8 represents hydrogen or an alkyl group; the alkyl groups of R˜R7,and R8 are linear or branched, having one to four carbon atoms, thealkyl groups of R6 and R7 optionally being joined to form a five or sixmember saturated ring; the aryl substituent of R6 and the aryl group ofR7 are phenyl, pyridinyl, pyrrolyl, or furanyl.
 11. A compound accordingto claim 10, wherein the acetallketal protecting groups are selectedfrom the group consisting of methoxymethyl, ethoxymethyl,tetrahydropyranyl, and benzyloxymethyl.
 12. A compound according toclaim 10, wherein the acetallketal protecting group is methoxymethyl.13. A compound according to claim 9, wherein the acetallketal protectinggroups are selected from the group consisting ofp-methoxybenzyloxymethyl and betatrimethylsilyloxyethoxymethyl groups.14. A compound according to claim 2, wherein the protecting group is amember of the class of arylmethyl protecting groups, wherein the arylgroup is phenyl, pyridinyl, pyrrolyl, or furanyl, optionally substitutedwith methoxy, ethoxy, nitro, or halo.
 15. A compound according to claim14, wherein the protecting group is selected from the group consistingof benzyl, p-methoxybenzyl, and p-ethoxybenzyl.
 16. A compound accordingto claim 15, wherein the protecting group is pmethoxybenzyl.
 17. Acompound according to claim 2, wherein R2 is a leaving group and R3 is amethyl group.
 18. A compound according to claim 17, wherein R2 is C1.19. A compound according to claim 17, wherein R2 is Br.
 20. A compoundaccording to claim 17, wherein R2 is I.
 21. A compound according toclaim 17, wherein R2 is a sulfonate ester group.
 22. A compoundaccording to claim 21, wherein the sulfonate ester group is selectedfrom triflate, mesylate, benzensulfonate and tosylate.
 23. A compoundaccording to claim 17, wherein R2 is a phosphate ester group.
 24. Acompound according to claim 20, wherein R3 is methyl.
 25. A compoundaccording to claim 20, wherein R3 is H.
 26. A compound according toclaim 1, having the formula:


27. A compound according to claim 1, having the formula:

wherein R′ is H or a protecting group, R2 and R3 each independentlyrepresent H, methyl, or a leaving group, provided that at least one, butnot both, of R2 and R3 is a leaving group.